(Applicant's Abstract) Heroin, cocaine, and alcohol addictions, alone and in combination, along with their frequent medical complications, including hepatitis B, C, AIDS, and psychiatric co-morbidity, remain the major medical problems confronting our nation. Effective treatments must be based on a fundamental understanding of the biological basis of each specific addictive disease, including the effects of drugs of abuse, and inherent and environmental factors which may increase vulnerability prior to exposure to drugs of abuse. Our NIH-NIDA Treatment Research Center will continue to identify and study the biological correlates of the addictions and factors which might affect treatment outcome. In this proposal for the continuation of our ongoing Center, all laboratory and clinical research studies have been developed on an interactive basis, relying upon the Center for their integration. Translational research is a hallmark of the work of the Center. Research findings and observations from the basic and applied clinical research are used to formulate specific hypotheses to be tested in laboratory research. Conversely, findings from laboratory research, including studies conducted in appropriate models, will be applied, as promptly as feasible and appropriate, into clinical research, and then on into the clinic. The specific projects proposed include: (1) effects of drugs of abuse and potential therapeutic agents on the molecular biology of the endogenous opioids, related neuropeptides and their receptors; 2) effects of drugs of abuse and potential therapeutic agents on opioid receptors and peptides and on related neurotransmitter systems; 3) disposition and biotransformation of natural and synthetic opioid agonists, antagonists and related peptides: interactions and effects; 4) effects of drugs of abuse and potential therapeutic agents on the molecular biology and expression of the stress responsive hypothalamic-pituitary adrenal axis.; 5) neuroendocrine effects of addictive drugs: role of the endogenous opioids and stress responsivity in addictive diseases; 6) interactions of NMDA and mu opioid receptors. These scientific projects will be integrated through the Core Resources, strengthening interactions which only a Center can provide.